The PC-12 pheochromocytoma and several neuroblastoma cell lines possess specific receptors for both nerve growth factor (NGF) and epidermal growth factor (EGF). PC-12 cells, which differentiate morphologically and biochemically into sympathetic neuron-like cells in response to NGF, will respond to EGF with an increase in cell proliferation. NGF induces the formation of neurites while EGF does not. The simultaneous addition of EGF and NGF results in cells with morphological characteristics indistinguishable from those of cells treated with NGF alone. It is unclear as to why the NGF response dominates in this situation of both a proliferation and a differentiation signal being received by the same cell. Apparently NGF, by an unknown mechanism, is able to attenuate signaling and/or responses due to EGF binding to its receptor. It is known that pre-treatment of cells with NGF for 72 hours reduces the amount of 125I-EGF binding by at least 80%, due to a presumed reduction in the number of binding sites, as inferred by Scatchard analysis. Short-term responses to EGF, such as the induction of ornithine decarboxylase, are also blocked by a brief pre-treatment with NGF at a concentration whish is insufficient to cause a large decrease in 125I-EGF binding capacity. Similar results have been obtained with neuroblastoma cells. The action of NGF appears to predominate over that of EGF through some unknown mechanism. The overall objective of this research proposal is to investigate the modulation of the EGF receptor by NGF, and to discover what other factors play a role in this selection phenomenon that determines a cell's commitment to differentiation rather than proliferation. Specifically, NGF regulation of the EGF receptor will be studied at the mRNA and protein levels to determine whether NGF produces a decline in EGF receptor synthesis that parallels the loss of binding capacity. The EGF receptor in PC-12 cells will also be examined to determine whether short-term exposure to NGF attenuates the physiology (e.g. internalization) and biochemistry (e.g. tyrosine kinase activity) of the EGF receptor. Fibroblast growth factor (FGF), another inducer of neurite formation in PC-12 cells, will also be investigated as a potential modulator of the EGF receptor. Transition of the candidate from Phase I to Phase II of this research plan will be clearly decided by Dr. Brown's completion of the Ph.D. requirements and dissertation defense. Phase II will be basic research as a Ph.D. postdoctoral fellow.